EP2488519A1 - Dérivés de pyrazolopyridine comme agent anticancer - Google Patents

Dérivés de pyrazolopyridine comme agent anticancer

Info

Publication number
EP2488519A1
EP2488519A1 EP10770774A EP10770774A EP2488519A1 EP 2488519 A1 EP2488519 A1 EP 2488519A1 EP 10770774 A EP10770774 A EP 10770774A EP 10770774 A EP10770774 A EP 10770774A EP 2488519 A1 EP2488519 A1 EP 2488519A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
group
aryl
heterocycle
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP10770774A
Other languages
German (de)
English (en)
Other versions
EP2488519B1 (fr
Inventor
Karim Bedjeguelal
Rémi RABOT
El Bachir Kaloun
Patrice Mayer
Arnaud Marchand
Nicolas Rahier
Philippe Schambel
Hugues Bienayme
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pierre Fabre Medicament SA
Original Assignee
Pierre Fabre Medicament SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Medicament SA filed Critical Pierre Fabre Medicament SA
Publication of EP2488519A1 publication Critical patent/EP2488519A1/fr
Application granted granted Critical
Publication of EP2488519B1 publication Critical patent/EP2488519B1/fr
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention concerns pyrazolopyridine derivatives, their therapeutic use notably for cancer treatment, and their method of synthesis.
  • Protein kinases are enzymes which play a key role in cell signal transduction, and are involved in physiological processes such as cell proliferation, mitosis, differentiation, cell invasion and mobility, or apoptosis. These enzymes are considered to play a major role during the different stages of tumour development, and therefore form important pharmaceutical targets for the treatment of cancers.
  • Receptor tyrosine kinases form a particular class of protein kinases amongst which mention may be made inter alia of: ALK, EGFR, HER2, PDGFR, KIT, VEGFR, IGFR, FGFR, TRK, AXL, MER, MET, RON and RET.
  • ALK is considered to be a particularly relevant target since able to give rise to activating chromosome translocation, generating tumorigenesis.
  • the fusion protein NPM-ALK is associated with Anaplastic Large Cell Lymphoma (ALCL) for which optimal treatment remains to be developed.
  • the fusion protein EML4-ALK is associated with tumoral development in a sub-population of patients suffering from non-small cell lung cancer. Mutant forms of ALK have also been observed in neuroblastoma.
  • the compounds of the present invention therefore have the property of inhibiting or modulating the enzymatic activity of protein kinases, e.g. ALK, and therefore can be used as medicinal product, for example for the treatment of various diseases notably proliferative diseases such as cancer, inflammation or disorders of the central nervous system.
  • protein kinases e.g. ALK
  • a particular subject of the invention is therefore a compound of following general formula (I): or a pharmaceutically acceptable salt thereof,
  • halogen atom such as a chlorine atom, or a 20 21 21
  • the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom and a -OH, -CN, -N0 2 , -NH 2 , - C0 2 H, (Ci-C 6 )alkyl optionally substituted with an OH group, (Ci-C 6 )alcoxy, (Q- C 6 )haloalkyl, (C 1 -C 6 )haloalcoxy, aryl, aryloxy, aryl-(C 1 -C 6 )alkyl, aryl-(Ci- C 6 )alcoxy, heteroaryl, heterocycle, -C0 2 -((C 1 -C 6 )alkyl), aryl-carbonyloxy, -NH- ((Ci-C 6 )alkyl), and -NHS0 2 -((C 1 -C 6 )alkyl) group; and/or being optionally fused to
  • - R is a hydrogen atom, a (Ci-C 6 )-alkyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl 1 lkyl 2 -(C 1 -C 6 )alkyl, aryl-(C 1 -C 6 )alkenyl, -X -heterocycle, -cycloa -X - heterocycle, and -cycloalkyl-((C 1 -C 6 )alkyl)-OH group,
  • the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH; N0 2 ; C0 2 H; CN; CONH 2 ; S0 3 H; (Ci- alkyl optionally substituted with an OH group; (Q- C 6 )alkynyl optionally substituted with an NR 25 R 26 group; (C 1 -C 6 )alcoxy; aryl optionally substituted with NH 2 and/or S0 2 NH 2 ; heteroaryl; heterocycle; aryl-(Ci- C 6 )alkyl; heteroaryl-(C 1 -C 6 )alkyl; heterocycle-(C 1 -C 6 )alkyl; aryl-(Ci-C 6 )alcoxy; heteroaryl-(C 1 -C 6 )alcoxy; heterocycle-(C 1 -C 6 )alcoxy; NR 10 R n ; and
  • heterocycle rings of the whole being optionnaly substituted with one or more groups chosen from among OH; (Ci-C 6 )alkyl optionally substituted with OH or NR 27 R 28 such as NH 2 ; C0 2 -((C 1 -C 6 )alkyl); heterocycle optionally substituted with a (C 1 -C 6 )alkyl group; and NR 14 R 15 ,
  • - R is a hydrogen atom, a group NH 2 ; N0 2 ; C0 2 H; (Q-C ⁇ alkyl optionally substituted with a group OR 22 or NR 23 R 24 ; CONH-((C 1 -C 6 )alkyl); CONH-((Ci- C 6 )alkyl)-heterocycle; aryl; heteroaryl; heterocycle; aryl-(C 1 -C 6 )alkyl; -NH-aryl; or -NH-heteroaryl,
  • the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom; a N0 2 ; C0 2 H; NR 16 R 17 ; aryl; (Q- C 6 )alkyl; (Q-C f haloalkyl; (Ci-C 6 )alcoxy; -C0 2 -(C 1 -C 6 )alkyl; and heterocycle group, and
  • heterocycle rings of the whole being optionally substituted with a (Q-C ⁇ alkyl; (C 1 -C 6 )alcoxy; or -NH-(Ci-C 6 )alkyl group, and
  • R 4 is a hydrogen atom, a (Ci-C 6 )alkyl group such as methyl or tert-butyl, or an aryl group such as phenyl, and preferably is a hydrogen atom,
  • X 1 and X 2 are each independently -CO-, -CONH- or -CONH-((C 1 -C 6 )alkyl),
  • X is a single bond, an oxygen atom, a sulphur atom, a NH or N-((C 1 -C 6 )alkyl) group,
  • R 10 , R 11 , R 14 , R 15 , R 18 , R 19 , and R 23 to R 28 are each independently a hydrogen atom or a (C 1 -C 6 )alkyl group,
  • R 12 and R 13 are each independently a hydrogen atom or a (Ci-C 6 )alkyl group; or form together, with the nitrogen atom bearing them, a heteroaromatic or a heterocycle optionally substituted with a (Ci-C 6 )alkyl group,
  • R 16 and R 17 are each independently a hydrogen atom or a (Ci-C 6 )alkyl group optionally substituted with a group NR 18 R 19 ,
  • R 20 is a hydrogen atom or a (Ci-C 6 )alkyl, aryl, or aryl-(C 1 -C 6 )alkyl group, and
  • R 21 and R 2"2 are each independently a hydrogen atom or (Ci-Ce-alkyl), aryl, or heteroaryl group, the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH, CN, N0 2 , NH 2 , C0 2 H, (Ci-C 6 )alkyl, (d-C 6 )alcoxy, (d-C 6 )haloalkyl, (d-C 6 )haloalcoxy, aryl, aryloxy, aryl-(C 1 -C 6 )alkyl, aryl-(Ci-C 6 )alcoxy, heteroaryl, heterocycle, C0 2 -((Ci- C 6 )alkyl); NH-((Ci-C 6 )alkyl), and NHS0 2 -((Ci-C 6 )alkyl); and/or being optionally fused to
  • pharmaceutically acceptable is meant what can be used to prepare a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use and for human pharmaceutical use.
  • salts which are pharmaceutically acceptable, as defined herein, and which have the desired pharmacological activity of the parent compound.
  • Such salts comprise:
  • the salts formed when an acid proton present in the parent compound is either replaced by a metallic ion e.g. an alkaline metal ion, an alkaline-earth metal ion or an aluminium ion; or is coordinated with an organic or inorganic base such as potassium hydroxide or sodium hydroxide.
  • a metallic ion e.g. an alkaline metal ion, an alkaline-earth metal ion or an aluminium ion
  • an organic or inorganic base such as potassium hydroxide or sodium hydroxide.
  • halogen atom is meant, in the meaning of the present invention, fluorine, chlorine, bromine and iodine atoms.
  • (C 1 -C 6 )alkyl is meant, in the meaning of the present invention, a saturated, linear or branched hydrocarbon chain comprising 1 to 6, preferably 1 to 4, carbon atoms.
  • the following groups may be cited: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyle, and hexyl.
  • (C 2 -C 6 )alkenyl group, in the meaning of the present invention, a linear or branched hydrocarbon chain comprising at least one double bond and containing 2 to 6 carbon atoms.
  • (C 2 -C 6 )alkynyl is meant, in the meaning of the present invention, a linear or branched hydrocarbon chain comprising at least one riple bond and containing 2 to 6 carbon atoms.
  • (C 1 -C 6 )alcoxy group, in the meaning of the present invention, a (Ci-C 6 )alkyl group such as defined above, linked to the remainder of the molecule via an oxygen atom.
  • a (Ci-C 6 )alkyl group such as defined above, linked to the remainder of the molecule via an oxygen atom.
  • (C 1 -C 6 )halooalkyl is meant, in the meaning of the present invention, a (Ci-C 6 )alkyl group such as defined above in which one or more hydrogen atoms have been replaced by a halogen atom as defined above. This may be in particular a CF 3 group.
  • (Ci-Ce ⁇ aloalcoxy) group is meant in the meaning of the present inventions (C 1 -C 6 )haloalkyl group such as defined above, linked to the remainder of the molecule via an oxygen atom.
  • aryl is meant, in the meaning of the present invention,an aromatic group preferably comprising 6 to 10 carbon atoms and containing one or more fused cycles, such as a phenyl or naphtyl group.
  • aryloxy group is meant, in the meaning of the present invention, any aryl group such as defined above, linked to the molecule via an oxygen atom. It may be in particular a phenyloxy group.
  • heteroaryl or “heteroaromatic” is meant, in the meaning of the present invention, an aromatic group comprising 5 to 10 cyclic atoms including one or more heteroatoms, advantageously 1 to 4 and more advantageously 1 or 2, such as sulphur, nitrogen or oxygen atoms for example, the other cyclic atoms being carbon atoms.
  • heteroaryl groups are the furyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, or indyl groups.
  • heterocycle is meant, in the meaning of the present invention, a 3- to 7- membered cycle saturated or unsaturated but not aromatic, and containing one or more, advantageously 1 to 4, more advantageously 1 or 2, heteroatoms such as sulpur, nitrogen or oxygen atoms for example.
  • heteroatoms such as sulpur, nitrogen or oxygen atoms for example.
  • These may be particularly the pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl groups.
  • cycloalkyl is meant, in the meaning of the present invention, a cyclic saturated hydrocarbon chain comprising 3 to 7 cyclic carbon atoms. Examples are the cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl groups.
  • aryl-(C 1 -C 6 )alkyl is meant, in the meaning of the present invention, an aryl group such as defined above, linked to the remainder of the molecule via a (C - C 6 )alkyl chain such as defined above.
  • the benzyl group can be cited.
  • aryl-(C 1 -C 6 )alkenyl is meant, in the meaning of the present invention, an aryl group such as defined above, linked to the remainder of the molecule via a (Ci- C 6 )alkenyl chain such as defined above.
  • aryl-ethenyl is meant, in the meaning of the present invention, an aryl group such as defined above, linked to the remainder of the molecule via a (Ci- C 6 )alkenyl chain such as defined above.
  • aryl-(C 1 -C 6 )alcoxy is meant, in the meaning of the present invention, an aryl-(C 1 -C 6 )alkyl group such as defined above, linked to the reaminder of the molecule via an oxygen atom.
  • the benzyloxy group can be mentioned.
  • heteroaryl-(C 1 -C 6 )alkyl is meant, in the meaning of the present inventions heteroaryl group such as defined above, linked to the remainder of the molecule via a (Ci-C 6 )alkyl chain such as defined above.
  • heteroaryl-(C 1 -C 6 )alcoxy is meant, in the meaning of the present invention, a heteroaryl-(C 1 -C 6 )alkyl group such as defined above, linked to the reaminder of the molecule via an oxygen atom.
  • heterocycle-(C 1 -C 6 )alkyl is meant, in the meaning of the present invention, a heterocycle group such as defined above, linked to the remainder of the molecule via a (Ci-C 6 )alkyl chain such as defined above.
  • heterocycle-(C 1 -C 6 )alcoxy is meant, in the meaning of the present invention, a heterocycle-(C 1 -C 6 )alkyl group such as defined above, linked to the remainder of the molecule via an oxygen atom.
  • arylcarbonyloxy is meant, in the meaning of the present invention, an aryl group such as defined above, linked to the molecule via a -C(0)0- group.
  • aryl-carbonyloxy group can be cited.
  • R 1 is a halogen atom such as a chlorine atom, or a NHR 20 , OR 21 , SR 21 , (Ci-C 6 )alkyl, aryl, heteroaryl, aryl-(C 1 -C 6 ))alkyl, heterocycle, or aryl-carbonyloxy group, and preferably is a halogen atom such as a chlorine atom, or a NHR 20 , SR 21 , (Q- C 6 )alkyl, aryl, heteroaryl, aryl-(C 1 -C 6 ))alkyl, heterocycle, or aryl-carbonyloxy group,
  • the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom and a -OH, -CN, -N0 2 , -NH 2 , - C0 2 H, (Ci-C 6 )alkyl, (d-C 6 )alcoxy, (d-C 6 )haloalkyl, (d-C 6 )haloalcoxy, aryl, aryloxy, aryl-(C 1 -C 6 )alkyl, aryl-(Ci-C 6 )alcoxy, heteroaryl, heterocycle, -C0 2 -((Ci- C 6 )alkyl), -NH-((C 1 -C 6 )alkyl), and -NHS0 2 -((C 1 -C 6 )alkyl) group; and/or being optionally fused to a heterocycle, and the heterocycle rings of the whole being optionally substituted with one or
  • - R is a hydrogen atom, a (Ci-C 6 )-alkyl, aryl, heteroaryl, cycloalkyl, heterocycle, aryl-(C 1 2 1-C 6 )alkyl, aryl-(C 1 -C 6 )alkenyl, -X -heterocycle, -cycloalkyl-X - heterocycle, and -cycloalkyl-((C 1 -C 6 )alkyl)-OH group, the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH; N0 2 ; C0 2 H; CN; CONH 2 ; S0 3 H; (C 1 -C 6 )alkyl optionally substituted with an OH group; (Q- C 6 )alcoxy; aryl optionally substituted with S0 2 NH 2 ; heteroaryl; heterocycle; aryl- (Ci
  • - R is a hydrogen atom, a group NH 2 ; N0 2 ; C0 2 H; (Q-C ⁇ alkyl optionally substituted with a group OR 22 or NR 23 R 24 ; CONH-((Ci-C 6 )alkyl); CONH-((Ci- C 6 )alkyl)-heterocycle; aryl; heteroaryl; heterocycle; aryl-(C 1 -C 6 )alkyl; -NH-aryl; or -NH-heteroaryl,
  • the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom; a N0 2 ; C0 2 H; NR 16 R 17 ; aryl; (Q- C 6 )alkyl; (Q-C f haloalkyl; (Ci-C 6 )alcoxy; -C0 2 -(C 1 -C 6 )alkyl; and heterocycle group, and
  • R 4 is a hydrogen atom, a (Ci-C 6 )alkyl group such as methyl or tert-butyl, or an aryl group such as phenyl, and preferably is a hydrogen atom.
  • R° is a -CN; -C0 2 H; -C0 2 -((C 1 -C 6 )alkyl); -S0 2 ((Ci-
  • C 6 )alkyl) group in particular a -CN or -C0 2 -((Ci-C 6 )alkyl) group such as COOEt; for example a CN group.
  • R 1 is advantageously an aryl group such as phenyl or naphtyl, or a heteroaryl group such as furyl, thienyl, pyrrole, indolyl, benzoimidazolyl, indazolyl or benzotriazolyl, and is preferably an aryl group such as phenyl, said group being optionally substituted with one or more groups chosen from among a halogen atom, a OH, CN, N0 2 , NH 2 , C0 2 H, (C 1 -C 6 )alkyl optionally substituted with an OH group, (C 1 -C 6 )alcoxy, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )haloalcoxy, aryl, aryloxy, aryl- (Ci-C 6 )alkyl, aryl-(Ci-C 6 )alcoxy, heteroaryl, heterocycle, C0 2 -(
  • R is an aryl or heteroaryl group, said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH; N0 2 ; C0 2 H; CN; CONH 2 ; S0 3 H; (C 1 -C 6 )alkyl optionally substituted with an OH group; (Q-C ⁇ alkynyl optionally substituted with an NR 25 R 26 group; (C 1 -C 6 )alcoxy; aryl optionally substituted with NH 2 and/or S0 2 NH 2 ; heteroaryl; heterocycle; aryl-(Ci- C 6 )alkyl; heteroaryl-(C 1 -C 6 )alkyl; heterocycle-(C 1 -C 6 )alkyl); aryl-(Ci-C 6 )alcoxy; heteroaryl-(C 1 -C 6 )alcoxy; heterocycle-(C 1 -C 6 )alcoxy; NR 10
  • heterocycle rings of the whole being optionally substituted with one or more groups chosen from among OH; (C 1 -C 6 )alkyl optionally substituted with OH or NR 27 R 28 ; C0 2 - ((C 1 -C 6 )alkyl); heterocycle optionally substituted with a (C 1 -C 6 )alkyl group; and NR 14 R 15 .
  • R is an aryl or heteroaryl group, said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH; N0 2 ; C0 2 H; CN; CONH 2 ; S0 3 H; (C 1 -C 6 )alkyl optionally substituted with an OH group; (C 1 -C 6 )alcoxy; aryl optionally substituted with S0 2 NH 2 ; heteroaryl; heterocycle; aryl-(C 1 -C 6 )alkyl; heteroaryl-(C 1 -C 6 )alkyl; heterocycle-(C 1 -C 6 )alkyl); aryl-(Ci- C 6 )alcoxy; heteroaryl-(C 1 -C 6 )alcoxy; heterocycle-(C 1 -C 6 )alcoxy; NR 10 R n ; and -X 3 -
  • ((C 1 -C 6 )alkyl)NR R and/or being optionally fused to a heterocycle, the heterocycle rings of the whole being optionally substituted with one or more groups chosen from among OH; (C 1 -C 6 )alkyl optionally substituted with OH or NH 2 ; C0 2 - ((C 1 -C 6 )alkyl); heterocycle optionally substituted with a (Ci-C 6 )alkyl group; and NR 14 R 15 .
  • R is a hydrogen atom, a group NH 2 , (Ci-C 6 )alkyl group such as methyl, aryl such as phenyl, or heteroaryl such as furanyl, thienyl, pyridinyl, isoxazolyl, thiazolyl or oxadiazolyl,
  • the aryl and heteroaryl rings being optionally substituted with one or more groups chosen from among a halogen atom or a N0 2 , C0 2 H, NR 16 R 17 , aryl, (C 1 -C 6 )alkyl, (Q- C 6 )haloalkyl, (C 1 -C 6 )alcoxy, C0 2 -(C 1 -C 6 )alkyl, and heterocyle group, the heterocycle rings being optionally substituted with a (Ci-C 6 )alkyl, (C 1 -C 6 )alcoxy, or NH-(Ci- C 6 )alkyl group.
  • R is a hydrogen atom, a NH 2 , (Ci-C 6 )alkyl, aryl, or heteroaryl group, and advantageously a hydrogen atom, a NH 2 , methyl, phenyl, thienyl, or furanyl group.
  • R 4 is a hydrogen atom.
  • the compound of the invention is a compound of general formula (I) or one of its pharmaceutically acceptable salts in which:
  • - R° is a -CN, -C0 2 H, -C0 2 -((Ci-C 6 )alkyl), or -S0 2 ((Ci-C 6 )alkyl) group; for example a -CN or -C0 2 ((C 1 -C 6 )alkyl) group such as -COOEt; for example -CN, - R 1 is a halogen atom such as a chlorine atom, or a group: NHR 20 , OR 21 , (Q- C 6 )alkyl, aryl, heteroaryl, aryl-(C 1 -C 6 )alkyl, or heterocycle; for example an aryl group such as phenyl or naphtyl, or a heteroaryl group such as furyl, thienyl, pyrrole, indolyl, benzoimidazolyl, indazolyl or benzotriazolyl; for example phenyl, the
  • R is a hydrogen atom, a (Ci-C 6 )alkyl; aryl; heteroaryl; aryl-(C 1 -C 6 )alkyl; aryl-(Ci-
  • the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH; N0 2 ; C0 2 H; CN; CONH 2 ; S0 3 H; (Q-Ce kyl optionally substituted with a OH group; (Q- C 6 )alkynyl optionally substituted with an NR 25 R 26 group; (Ci-C 6 )alcoxy; aryl optionally substituted with NH 2 and/or S0 2 NH 2 ; heterocycle; heteroaryl-iCi- C 6 )alkyl; heterocycle-(C 1 -C 6 )alkyl; heterocycle-(C 1 -C 6 )alcoxy; NR 10 R U ; and -X 3 -
  • ((Ci-C 6 )alkyl)-NR R and/or being optionally fused to a heterocycle; and notably the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH; N0 2 ; C0 2 H; CN; CONH 2 ; S0 3 H; (C 1 -C 6 )alkyl optionally substituted with a OH group; (Q- C 6 )alcoxy; aryl optionally substituted with S0 2 NH 2 ; heterocycle; heteroaryl-(Ci- C 6 )alkyl; heterocycle-(C 1 -C 6 )alkyl; heterocycle-(C 1 -C 6 )alcoxy; NR 10 R U ; and -X 3 -
  • heterocycle rings of the whole being optionally substituted with one or more groups chosen from among OH; (Ci-C 6 )alkyl optionally substituted with OH or NR 27 R 28 such NH 2 ; C0 2 -((Ci-C 6 )alkyl); heterocycle optionally substituted with a(C 1 -C 6 )alkyl group; and NR 14 R 15 ;
  • - R 3 is a hydrogen atom, a group NH 2 , N0 2 , (Ci-Qdalkyl, CONH-((Ci-C6)alkyl), CONH-((C 1 -C 6 )alkyl)-heterocycle, aryl, heteroaryl, heterocycle, aryl-(C 1 -C 6 )alkyl, or -NH-heteroaryl; for example a hydrogen atom, a group NH 2 , (Q-C ⁇ alkyl (such as methyl), aryl (such as phenyl),
  • aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom, a group N0 2 , C0 2 H, NR 16 R 17 , aryl such as phenyl, (d-C 6 )alkyl, (Ci-C 6 )haloalkyl, (Ci-C 6 )alcoxy, -C0 2 -(Ci-C 6 )alkyl, and heterocycle,
  • heterocycle rings of the whole being optionally substituted with a (Ci-C 6 )alkyl, (C 1 -C 6 )alcoxy or -NH-(Ci-C 6 )alkyl group, and
  • R 4 is a hydrogen atom, a (Q-C ⁇ alkyl group (such as methyl or tert-butyl) or an aryl group such as phenyl; for example it is a hydrogen atom, wherein:
  • X 1 and X 2 are each independently -CO-, -CONH- or -CONH-((C 1 -C 6 )alkyl),
  • X is a single bond, an oxygen atom, a sulphur atom or N-((Ci-C 6 )alkyl),
  • R 10 , R 11 , R 14 , R 15 , R 18 , R 19 and R 23 and R 28 are each independently a hydrogen atom or a (Ci-C 6 )alkyl group
  • R 12 and R 13 are each independently a hydrogen atom or a (Ci-C 6 )alkyl group; or form together, with the nitrogen atom bearing them, a heterocycle,
  • R 16 and R 17 are each independently a hydrogen atom or a (Ci-C 6 )alkyl group optionally substituted with a NR 18 R 19 group,
  • R 18 and R 19 are each independently a hydrogen atom or a (Ci-C 6 )alkyl group
  • ⁇ R 20 is a hydrogen atom or a (Ci-C 6 )alkyl, aryl, or aryl-(Ci-C 6 )alkyl group
  • R 21 is a hydrogen atom or a (Ci-C 6 )alkyl, aryl, or heteroaryl group,
  • the aryl and heteroaryl rings of said group being optionally substituted with one or more groups chosen from among a halogen atom, a group OH, CN, N0 2 , NH 2 , C0 2 H, (C 1 -C 6 )alkyl, (Q-Ce coxy, (Ci-Ce ⁇ aloalkyl, (Ci-Ce ⁇ aloalcoxy, aryl, aryloxy, aryl-(Ci-C 6 )alkyl, aryl-(Ci-C 6 )alcoxy, heteroaryle, heterocycle, C0 2 -((Ci-
  • the compounds of the invention may meet the following formula (la):
  • R 2" and R 3 J are such as defined previously, and
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently a hydrogen atom, a halogen atom, a group OH; CN; N0 2 ; NH 2 ; C0 2 H; (C 1 -C 6 )alkyl optionally substituted with an OH group; (C 1 -C 6 )alcoxy; (Ci-Ce ⁇ aloalkyl; (Ci-Ce ⁇ aloalcoxy; aryl; aryloxy; aryl- (Ci-C 6 )alkyl; aryl-(Ci-C 6 )alcoxy; heteroaryl; heterocycle; C0 2 -((C 1 -C 6 )alkyl); aryl-carbonyloxy; NH-((C 1 -C 6 )alkyl), and NHS0 2 -((C 1 -C 6 )alkyl); and notably are each independently a hydrogen atom, a halogen atom,
  • the compounds of the invention may in particular be chosen from among the compounds cited in following Table 1 :
  • a further subject of the invention is a compound of formula (I) such as defined above, including the following compounds:
  • the present invention also concerns the use of a compound of formula (I) such as defined above, including the following compounds:
  • the present invention also concerns a method to treat cancer, comprising the administration to a person in need thereof of an efficient dose of a compound of formula (I) such as defined above, including the following compounds:
  • the present invention also concerns a pharmaceutical composition containing at least one compound of formula (I) such as defined above, including the following compounds:
  • compositions of the invention can be formulated in particular for oral administration or for injection, said compositions being intended for mammals, including man.
  • the active ingredient can be administered in unit administration forms in a mixture with conventional pharmaceutical carriers, to animals and to human beings.
  • the compounds of the invention as active ingredients can be used at doses from 0.01 mg to 1,000 mg per day, given in a single dose per day or administered in several doses throughout the day, for example twice a day in equal doses.
  • the dose administered per day is advantageously between 5 mg and 500 mg, more advantageously between 10 mg and 200 mg. It may be necessary to use doses outside these ranges as can be ascertained by the person skilled in the art.
  • compositions of the invention may further comprise at least one other active ingredient such as an anticancer agent.
  • a further subject of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the present invention also concerns a pharmaceutical composition such as defined above for its use as medicinal product notably intended for the treatment of a cancer.
  • a further subject of the invention is a method to prepare a formula (I) compound, said method comprising a condensation reaction between:
  • the oxidation reaction can be conducted in the presence of a usual oxidant well known to the person skilled in the art, such as Mn0 2 , CAN or DDQ.
  • condensation reaction to give pyrazolopyridines can be depicted by the following scheme given by way of indication, bearing in mind that the first step can be obtained following the method described in international application WO 2004/14910 of Mitsubishi.
  • Step 1) Formation of the intermediate of formula (VI) by reaction of a methylene group activated by a electro-attractor group of formula (II) with the aldehyde of formula (III) optionally in the presence of a basic, acid, or metallic catalyst of mineral type such as potassium carbonate.
  • the reaction is conducted in any type of solvent (acetonitrile, butanol, ethanol, etc.) notably at a temperature of between 0°C and the boiling point of the solvent, and optionally in the presence of molten salt such as NH 4 OAc.
  • Step 2) Cyclizing condensation of the intermediate of formula (VI) with aminopyrazole (IV) under the same conditions as in step 1, to form the dihydropyridine of formula (V).
  • Step 3) Oxidation of the product optionally in the presence of an oxidant such as Mn0 2 , CAN, DDQ, etc., to give the corresponding pyrazolopyridine in any type of solvent (CH 2 C1 2 , DMSO, etc.) notably at a temperature comprised between 0°C and the boiling point of the solvent.
  • an oxidant such as Mn0 2 , CAN, DDQ, etc.
  • the cyanomethyl derivatives used as starting products for the preparation of pyrazolopyridines can be prepared following the method described in J. Org. Chem, 46, 783, 1981 ; Eur. J. Med. Chem., 31, 3, 1996; Tetrahedron Lett., 24, 5023, 1983 (whose teaching is incorporated by reference in the present application) by reaction of an ester with acetonitrile in the presence of an organometallic derivative of an alkaline metal, such as the alkyllithiums (N-butyllithium), in an organic solvent such as tetrahydrofuran, at low temperature.
  • an organometallic derivative of an alkaline metal such as the alkyllithiums (N-butyllithium)
  • organic solvent such as tetrahydrofuran
  • This mixture is stirred 2h at -78°C then a 1M hydrochloric acid solution is added, and the product is extracted several times with ethyl acetate.
  • the organic phases are combined before adding 3.5 ml of a tetrabutylammonium fluoride solution (1M in tetrahydrofuran).
  • the reaction mixture is stirred for 30 min at room temperature then water is added.
  • the product is extracted several times with ethyl acetate.
  • the organic phases are combined, dried over magnesium sulfate, and concentrated.
  • keto-esters used as starting material to obtain pyrazolopyridines can be prepared following the method described in the literature by Clay Ronald J., Synthesis, 1993, 3, 290-2 (whose teaching is incorporated in the present application by reference).
  • keto-sulfones used as starting material to obtain the pyrazolopyridines can be prepared following the method inspired from the literature by Ibarra C. Alvarez et al, Journal of Organic Chemistry, 1989, 54(23), 5620-3 (whose teaching is incorporated in the present application by reference).
  • S0 2 Me2 can be replaced by S0 2 Me((C 1 -C6)alkyl) to obtain keto-sulfones with alkyl substituents other than methyl by following the protocol described in Jeffrey et al, Tetrahedron 1984, 40, 1135-1140].
  • aldehydes are products well known to the person skilled in the art, and can be prepared using various methods described in the literature. Below a description is given of the aldehydes and their methods of preparation which are not described in the literature and used in the present invention.
  • the filtrate is concentrated and diluted in a sodium hydroxide solution (1M) and the product is extracted several times with ethyl acetate.
  • the organic phases are combined, dried over magnesium sulfate, and concentrated.
  • the residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 4:6 to 100% ethyl acetate) to yield 0.58 g of tert-butyl 4-(3-(4-formylphenoxy)propyl)piperazine-l-carboxylate in the form of a colourless oil.
  • N-methoxy-N-methyl-5-nitro- 1 H-pyrazol-3-carboxamide To 20.4 g (130.31 mmol) of 5-nitro-lH-pyrazole-3-carboxylic acid in suspension in 530 ml of 1,2-dichloroethane, are respectively added 28.36 ml (390.93 mmol) of thionyl chloride and 4 ml of dimethylformamide. The suspension is stirred under reflux for 8h. The reaction mixture is then cooled to room temperature and the precipitate is filtered.
  • the precipitate is re-suspended in 330 ml of dichloromethane after which are successively added 15.25 g (156.37 mmol) of ⁇ , ⁇ - dimethylhydroxylamine hydrochloride and 39.56 g (390.93 mmol) of triethylamine.
  • the reaction mixture is stirred for 18h at room temperature, water is added and the product is extracted several times with dichloromethane then with a dichloromethane/methanol mixture (90: 10).
  • the organic phases are combined, dried over magnesium sulfate and concentrated to yield 23.88 g of N-methoxy-N-methyl-5-nitro-lH-pyrazol-3- carboxamide in the form of a white solid.
  • reaction mixture is sonicated for 5 min then stirred at room temperature for 20h. It is filtered on silica (cyclohexane/ethyl acetate eluent: 6:4) to yield 2 g (91%) of ethyl 4-(4-(4-(tert-butoxycarbonyl)piperazin-l- yl)phenyl)-3-methyl-6-(2,3,6-trifluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5- carboxylate in the form of a yellow solid.
  • the mixture is diluted with 100 ml of ethyl acetate and the mixture is successively washed with water, a saturated NaHC0 3 solution and a sodium chloride saturated solution.
  • the organic phase is dried over sodium sulfate, filtered, and concentrated.
  • the ethyl 2-(4-methoxybenzoyl)-3-(5- methylfuran-2-yl) acrylate is used in the following step without purification.
  • reaction mixture is stirred for 48h, then the solid formed is filtered and rinsed several times in an acetonitrile/methanol (95:5) mixture and dried to yield 0.572 g of 3-methyl-4-(4- (piperazin- l-yl)phenyl)-6-(2,3 ,6-trifluorophenyl)- 1 H-pyrazolo [3 ,4-b]pyridine-5- carbonitrile hydrochloride in the form of a beige solid.
  • tert-butyl 4-(4-(6-(4-(benzyloxy)-3- methylphenyl)-5-cyano-3-(furan-2-yl)- 1 H-pyrazolo [3 ,4-b]pyridine-4- yl)phenyl)piperazine-l-carboxylate in a MeOH/CH 2 Cl 2 mixture are added 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene.
  • the mixture is refluxed for 18h, then 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4-cyclohexadiene are added, and the mixture is refluxed for an additional 24h, 0.41 g (0.38 mmol) of 10% Pd/C and 3 ml (2.57 g, 32.0 mmol) of 1,4- cyclohexadiene are added and the mixture is again refluxed for 24h. The mixture is then concentrated, dissolved in dichloromethane, filtered on Celite, then concentrated.
  • the reaction mixture is stirred 20h at room temperature.
  • the solvent is concentrated, water is added and the product extracted several times with ethyl acetate.
  • the organic phases are combined, dried over magnesium sulfate, and concentrated.
  • the residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 5:5 to 3:7) to yield 158 mg of tert-butyl 4-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3- methyl-lH-pyrazolo[3,4-b]pyridine-4-carbonyl)piperazine-l-carboxylate in the form of a white solid.
  • N-4-dimethyl- 1 H-pyrazolo[3,4-b]pyridine-3-carboxamide obtained following procedure Dl dissolved in 2 ml of ethanol are added 0.7 ml (8.39 mmol) of hydrazine hydrate. The solution is refluxed for 5h, 40 ml of water are added and the product is extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, and concentrated. The product is crystallized in methanol to yield 205 mg of 5-cyano-6-(2-fluoro-4-methoxyphenyl)-4-methyl-lH-pyrazolo[3,4- b]pyridine-3-carbohydrazide in the form of a white solid.
  • the solid is triturated in a diethyl ether/methanol mixture (10: 1) to yield 170 mg of 3-(5-(3- (diethylamino)propylamino)-l,3,4-oxadiazol-2-yl)-6-(2-fluoro-4-methoxyphenyl)- 4-methyl-lH-pyrazolo[3,4-b]pyridine-5-carbonitrile in the form of a pink solid.
  • tert-butyl 4-(4-(4-(tert-butoxycarbonyl)piperazin- l-yl)phenyl)-5-cyano-6-(2-fluoro-4-nitrophenyl)-3-methyl- 1 H-pyrazolo [3 ,4- b]pyridine-l-carboxylate is obtained by analogy with the method of Zhu, G.-D., Gong, J., Vogel, V.B., Woods, K., Luo, Y., Liu, X., Guan, R., Klinghofer, V., Johnson, E.F., Stoll, V.S., Mamo, M., Li, Q., Rosenberg, S.H., Giranda, V.L., Bioorg.
  • a ViewPlate (Packard) is incubated with the GST-PLCyl substrate (purified recombinant form) at 0.1 mg/ml in phosphate buffer (PBS pH 7.4)(100 ⁇ /well) for one hour under shaking. The plate is then saturated with a blocking solution containing 5% bovine serum albumin (BSA) (SIGMA) in PBS buffer pH 7.4.
  • BSA bovine serum albumin
  • the reaction is conducted by adding the ALK kinase at 180 ng/ml in 13 mM Tris reaction buffer pH 7.5 (SIGMA); 6.5 mM MgCl 2 (MERCK); 0.65 mM DiThioThreitol (DTT) (ACROS); 39 mM sodium ⁇ -glycerophosphate (TCI); 0.65 mM sodium orthovanadate (SIGMA) and 250 ⁇ ATP (SIGMA). Incubation is carried out for 30 minutes at 30°C under shaking.
  • SIGMA Tris reaction buffer pH 7.5
  • MERCK 6.5 mM MgCl 2
  • DTT DiThioThreitol
  • TCI sodium ⁇ -glycerophosphate
  • SIGMA sodium orthovanadate
  • SIGMA 250 ⁇ ATP
  • the signal is read in luminescent mode using a luminometer (MOLECULAR DEVICES
  • the antiproliferative activities of the compounds were measured using the ATPlite technique (Perkin Elmer).
  • the non-adhering cells (karpas 299) are seeded in 96-well plates (300 000 cells/ml) on Day 1 at a concentration compatible with logarithmic growth for 72 hours required for evaluation of the compounds. All the cells are treated on Day 1, then placed in an incubator at 37°C under 5% C0 2 atmosphere. Cell viability is evaluated on Day 4 by assay of released ATP, characteristic of viable cells.
  • the IC 50 values are determined by non-linear regression on the basis of a sigmoid model of dose/response relationship, Hill's slope coefficient being left variable, performed using GraphPad software sequence with the supplied algorithm.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des composés de formule générale suivante (I) : (Formule I) et sur leurs sels pharmaceutiquement acceptables, leur procédé de préparation et sur leurs utilisations, notamment comme agent anticancer.
EP10770774.7A 2009-10-13 2010-10-13 Dérivés de pyrazolopyridine comme agent anticancer Not-in-force EP2488519B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0957140A FR2951172B1 (fr) 2009-10-13 2009-10-13 Derives pyrazolopyridines en tant qu'agent anticancereux
US25428509P 2009-10-23 2009-10-23
PCT/EP2010/065346 WO2011045344A1 (fr) 2009-10-13 2010-10-13 Dérivés de pyrazolopyridine comme agent anticancer

Publications (2)

Publication Number Publication Date
EP2488519A1 true EP2488519A1 (fr) 2012-08-22
EP2488519B1 EP2488519B1 (fr) 2015-06-10

Family

ID=42112290

Family Applications (1)

Application Number Title Priority Date Filing Date
EP10770774.7A Not-in-force EP2488519B1 (fr) 2009-10-13 2010-10-13 Dérivés de pyrazolopyridine comme agent anticancer

Country Status (5)

Country Link
US (1) US8889711B2 (fr)
EP (1) EP2488519B1 (fr)
JP (1) JP5833010B2 (fr)
FR (1) FR2951172B1 (fr)
WO (1) WO2011045344A1 (fr)

Families Citing this family (49)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012088266A2 (fr) 2010-12-22 2012-06-28 Incyte Corporation Imidazopyridazines et benzimidazoles substitués en tant qu'inhibiteurs de fgfr3
DE102011105469A1 (de) * 2011-06-24 2012-12-27 Merck Patent Gmbh 7-Azaindolderivate
WO2013045413A1 (fr) * 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US10138235B2 (en) 2011-12-14 2018-11-27 Sanofi Pyrazolopyridine derivatives, preparation process therefor and therapeutic use thereof
FR2984325A1 (fr) * 2011-12-14 2013-06-21 Sanofi Sa Derives de pyrazolopyridine, leur procede de preparation et leur application en therapeutique
FR2985257B1 (fr) * 2011-12-28 2014-02-14 Sanofi Sa Composes dimeres agonistes des recepteurs des fgfs (fgfrs), leur procede de preparation et leur application en therapeutique
CN103214470A (zh) * 2012-01-18 2013-07-24 杨更亮 酮类与吲哚衍生物反应合成的新型抗癌化合物
WO2013167403A1 (fr) 2012-05-09 2013-11-14 Sanofi Dérivés de 6-(4-hydroxyphényl)-1h-pyrazolo[3,4-b]pyridine substitués utilisés comme inhibiteurs de kinases
EP3822273B1 (fr) 2012-06-13 2024-04-10 Incyte Holdings Corporation Composés tricycliques substitués servant d'inhibiteurs des fgfr
JPWO2013187462A1 (ja) 2012-06-14 2016-02-08 第一三共株式会社 ピペリジニルピラゾロピリジン誘導体
ES2637245T3 (es) 2012-06-29 2017-10-11 Pfizer Inc. Nuevas 4-(amino sustituido)-7H-pirrolo[2,3-d]pirimidinas como inhibidores de LRRK2
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9266892B2 (en) * 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
US9045477B2 (en) 2013-03-15 2015-06-02 Epizyme, Inc. Substituted 6,5-fused bicyclic heteroaryl compounds
EP2970306A4 (fr) 2013-03-15 2016-08-03 Epizyme Inc Composés hétéroaryles bicycliques substitués condensés en 6,5
TWI649318B (zh) 2013-04-19 2019-02-01 英塞特控股公司 作為ｆｇｆｒ抑制劑之雙環雜環
US9695171B2 (en) 2013-12-17 2017-07-04 Pfizer Inc. 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors
WO2016012896A1 (fr) 2014-07-24 2016-01-28 Pfizer Inc. Composés de pyrazolopyrimidine
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10221172B2 (en) 2015-01-13 2019-03-05 Vanderbilt University Benzothiazole and benzisothiazole-substituted compounds as mGluR4 allosteric potentiators, compositions, and methods of treating neurological dysfunction
PE20171514A1 (es) 2015-02-20 2017-10-20 Incyte Corp Heterociclos biciclicos como inhibidores de fgfr
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
WO2016205460A1 (fr) * 2015-06-16 2016-12-22 Nantbioscience, Inc. Dérivés polycycliques ciblant des gtpases ral et leurs applications thérapeutiques
BR112018000808A2 (pt) * 2015-07-16 2018-09-04 Array Biopharma Inc compostos de pirazolo[1,5-a]piridina substituída como inibidores de ret cinase
JP6873980B2 (ja) 2015-09-14 2021-05-19 ファイザー・インク ＬＲＲＫ２阻害薬としての新規のイミダゾ［４，５−ｃ］キノリンおよびイミダゾ［４，５−ｃ］［１，５］ナフチリジン誘導体
EP3483142A1 (fr) * 2016-07-05 2019-05-15 Guangzhou Maxinovel Pharmaceuticals Co., Ltd. Composé d'acétylène aromatique ou d'éthylène aromatique, produit intermédiaire, procédé de préparation, composition pharmaceutique et leur utilisation
TWI704148B (zh) 2016-10-10 2020-09-11 美商亞雷生物製藥股份有限公司 作為ｒｅｔ激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物
JOP20190077A1 (ar) 2016-10-10 2019-04-09 Array Biopharma Inc مركبات بيرازولو [1، 5-a]بيريدين بها استبدال كمثبطات كيناز ret
CN110267960B (zh) 2017-01-18 2022-04-26 阿雷生物药品公司 作为RET激酶抑制剂的取代的吡唑并[1,5-a]吡嗪化合物
AR111473A1 (es) * 2017-04-19 2019-07-17 Sumitomo Chemical Co Método para la preparación de compuesto de piridina
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
SG11202000602YA (en) 2017-08-01 2020-02-27 Theravance Biopharma R&D Ip Llc Pyrazolo and triazolo bicyclic compounds as jak kinase inhibitors
EP3733659B1 (fr) 2017-12-29 2023-12-20 Guangzhou Maxinovel Pharmaceuticals Co., Ltd. Dérivé de vinyle aromatique ou d'éthyle aromatique, procédé de préparation associé, intermédiaire, composition pharmaceutique et application
US11524963B2 (en) 2018-01-18 2022-12-13 Array Biopharma Inc. Substituted pyrazolo[3,4-d]pyrimidines as RET kinase inhibitors
CN111615514B (zh) 2018-01-18 2022-10-11 奥瑞生物药品公司 作为ret激酶抑制剂的取代的吡唑并[4,3-c]吡啶化合物
US11603374B2 (en) 2018-01-18 2023-03-14 Array Biopharma Inc. Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors
CR20200591A (es) 2018-05-04 2021-03-31 Incyte Corp Sales de un inhibidor de fgfr
AU2019262195A1 (en) 2018-05-04 2020-12-24 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11964988B2 (en) 2018-09-10 2024-04-23 Array Biopharma Inc. Fused heterocyclic compounds as RET kinase inhibitors
CA3125039A1 (fr) 2019-01-23 2020-07-30 Theravance Biopharma R&D Ip, Llc Imidazo[1,5-a]pyridine,1,2,4-triazolo[4,3-a]pyridine et imidazo[1,5-a]pyrazine utilisees en tant qu'inhibiteurs de jak
WO2020185532A1 (fr) 2019-03-08 2020-09-17 Incyte Corporation Méthodes de traitement du cancer au moyen d'un inhibiteur de fgfr
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
MX2022004513A (es) 2019-10-14 2022-07-19 Incyte Corp Heterociclos biciclicos como inhibidores de los receptores del factor de crecimiento de fibroblastos (fgfr).
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
EP4069696A1 (fr) 2019-12-04 2022-10-12 Incyte Corporation Hétérocycles tricycliques en tant qu'inhibiteurs de fgfr
PE20221504A1 (es) 2019-12-04 2022-09-30 Incyte Corp Derivados de un inhibidor de fgfr
WO2022261160A1 (fr) 2021-06-09 2022-12-15 Incyte Corporation Hétérocycles tricycliques en tant qu'inhibiteurs de fgfr
WO2024067773A1 (fr) * 2022-09-29 2024-04-04 Insilico Medicine Ip Limited Inhibiteurs de tead et méthodes d'utilisation associées

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE84533T1 (de) * 1985-12-13 1993-01-15 American Cyanamid Co Neue kondensierte pyridinverbindungen, zwischenverbindungen fuer die herstellung und ihre verwendung als herbizide wirkstoffe.
US4822799A (en) * 1988-01-27 1989-04-18 Sandoz Pharm. Corp. Pyrazolopyridine analogs of mevalonolactone and derivatives thereof useful for inhibiting cholesterol biosynthesis in mammals
WO2003068773A1 (fr) * 2002-02-12 2003-08-21 Glaxo Group Limited Derives de pyrazolopyridine
EP1537106A1 (fr) 2002-08-07 2005-06-08 Mitsubishi Pharma Corporation Composes de dihydropyrazolopyridine
US20040142978A1 (en) * 2002-12-12 2004-07-22 Pharmacia Corporation Aminocyanopyridine inhibitors of mitogen activated protein kinase-activated protein kinase-2
AU2004215644B2 (en) * 2003-02-27 2010-09-02 Palau Pharma, S.A. Pyrazolopyridine derivates
AU2004259012C1 (en) * 2003-07-23 2012-08-02 Exelixis, Inc. Anaplastic lymphoma kinase modulators and methods of use
EP1763528B1 (fr) * 2004-07-05 2008-11-26 Astellas Pharma Inc. Derives de pyrazolopyridine
JP2009506004A (ja) * 2005-08-25 2009-02-12 エフ．ホフマン−ラ ロシュ アーゲー ｐ３８ＭＡＰキナーゼ阻害剤としての縮合ピラゾール
WO2009006580A1 (fr) * 2007-07-05 2009-01-08 Cv Therapeutics, Inc. Dérivés de dihydropyridine, dihydropyrimidine et dihydropyrane facultativement condensés agissant comme bloqueurs des canaux calciques tardifs
US20100113415A1 (en) 2008-05-29 2010-05-06 Rajapakse Hemaka A Epha4 rtk inhibitors for treatment of neurological and neurodegenerative disorders and cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2011045344A1 *

Also Published As

Publication number Publication date
EP2488519B1 (fr) 2015-06-10
US20120245170A1 (en) 2012-09-27
JP5833010B2 (ja) 2015-12-16
US8889711B2 (en) 2014-11-18
FR2951172A1 (fr) 2011-04-15
FR2951172B1 (fr) 2014-09-26
WO2011045344A1 (fr) 2011-04-21
JP2013507425A (ja) 2013-03-04

Similar Documents

Publication Publication Date Title
WO2011045344A1 (fr) Dérivés de pyrazolopyridine comme agent anticancer
AU2022201082B2 (en) Benzimidazole compounds as c-Kit inhibitors
JP6068464B2 (ja) γ−セクレターゼ調節剤としての新規な置換インドール誘導体
AU2012241891B2 (en) Tri- and tetracyclic pyrazolo[3,4-b]pyridine compounds as antineoplastic agent
KR101529891B1 (ko) 폴리(ａｄｐ-리보스)폴리머라제(ｐａｒｐ)의 억제제로서의 피리디논 및 피리다지논 유도체
JP6285918B2 (ja) テトラヒドロピラゾロピリミジン化合物
RU2394825C2 (ru) Пирролопиразины, пригодные в качестве ингибиторов киназы аврора а
AU2016361441B2 (en) Bicyclic BET bromodomain inhibitors and uses thereof
JP2012514044A (ja) Ｒａｆキナーゼ阻害剤として有用なヘテロアリール化合物
BRPI1007018B1 (pt) Composto ligante de receptores de adenosina, composição farmacêutica, e, uso de um composto.
RU2579513C2 (ru) Ингибиторы активности акт
CA3085460A1 (fr) Derives d'amine aryl-bipyridine utilises en tant qu'inhibiteurs de la phosphatidylinositol phosphate kinase
JP2013512953A (ja) ピロロピリジンまたはベンゾイミダゾールコアを含有する複素環化合物
KR20200081436A (ko) 파르네소이드 x 수용체 조정제로서의 알켄 화합물
US20190263828A1 (en) Heteroaromatic compounds as vanin inhibitors
WO2019089672A1 (fr) Composés spirocycliques à utiliser en tant que modulateurs du récepteur farnésoïde x
JP2023518609A (ja) 新規アミノピリミジン系ｅｇｆｒ阻害剤
US20220370431A1 (en) C-myc mrna translation modulators and uses thereof in the treatment of cancer
JP2024500841A (ja) ｃＧＡＳと関連する病態の処置に有用なピロロ［３．２－ｂ］ピリジン誘導体
NZ619683B2 (en) Novel substituted indole derivatives as gamma secretase modulators

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20120328

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20130712

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20141211

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 730854

Country of ref document: AT

Kind code of ref document: T

Effective date: 20150715

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602010025183

Country of ref document: DE

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: NO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150910

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 6

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 730854

Country of ref document: AT

Kind code of ref document: T

Effective date: 20150610

REG Reference to a national code

Ref country code: NL

Ref legal event code: MP

Effective date: 20150610

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150911

Ref country code: RS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150910

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151010

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20150610

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151012

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602010025183

Country of ref document: DE

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

26N No opposition filed

Effective date: 20160311

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: LU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20151013

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151031

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151031

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20151013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20161013

Year of fee payment: 7

Ref country code: GB

Payment date: 20161014

Year of fee payment: 7

Ref country code: FR

Payment date: 20161028

Year of fee payment: 7

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SM

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20101013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: HR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602010025183

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20171013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20180629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180501

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20150610